RESUMO
Fanconi anemia (FA) is a rare disease characterized by progressive bone marrow failure, cancer predisposition, and multiple systemic malformations, including congenital abnormalities of the kidney and urinary tract (CAKUT). Hematopoietic cell transplantation (HCT), the only potentially curative treatment for the hematological complications of FA, may precipitate acute kidney injury (AKI) and hypertension. We retrospectively investigated 107 FA patients who underwent HCT between 2009 and 2017. We investigated the incidence and risk factors of AKI within 100 days after HCT in a cohort of FA patients, and kidney function and hypertension over 2-year follow-up.The incidence of AKI (mainly stage I) was 18.7%. Patients aged ≥ 11 years at transplantation showed a higher risk of AKI (OR 3.53). The eGFR was 60-90 mL/min/1.73 m2 in 53 (49.5%), 55 (51.4%), 50 (50.5%), 50 (51%), and 46 (59.7%) patients before HCT, at 100 days, 6 months, 1 year, and 2 years. Within the first 100 days after HCT, hypertension was observed in 72% of the patients and was associated with cyclosporine therapy. Most (62.3%) patients had stage 2 hypertension. CAKUT was observed in 33.7% of the patients and was associated with both hypertension (86%) and diminished kidney function but not with AKI.Conlusion: Although AKI, a commonly known HCT complication, was mild in this study, the prevalence of chronic kidney disease (CKD), as well as the high incidence of hypertension, specially associated with CAKUT point out the importance of kidney care in short and long-term follow up of FA patients. What is Known: ⢠Fanconi anemia (FA) is the most frequent inherited bone marrow failure in children, and 30% of cases have congenital anomalies of kidney (CAKUT). ⢠Acute kidney injury and hypertension after hematopoietic cell transplantation (HCT) may impact the outcomes.. What is New: ⢠Despite the presence of CAKUT and stage 2 CKD in 33.7% and 50% of the patients, respectively, AKI was mild and transitory after HCT in FA patients. ⢠CAKUT in FA patients was associated with lower kidney function and hypertension after HCT.
Assuntos
Injúria Renal Aguda , Anemia de Fanconi , Transplante de Células-Tronco Hematopoéticas , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Criança , Anemia de Fanconi/complicações , Anemia de Fanconi/epidemiologia , Anemia de Fanconi/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Rim , Estudos RetrospectivosRESUMO
Fanconi anemia (FA) is a rare inherited genetic condition that may lead to bone marrow failure, leukemia, and/or solid tumors. It is caused by the loss of function of at least 1 gene of the FA/BRCA pathway, which is necessary for DNA repair. Patients with FA have a 200-fold to 1000-fold risk of developing head and neck cancer, mainly oral squamous cell carcinoma (OSCC), and of doing so at a much younger age than individuals within the general population. Also, patients who have FA with OSCC have poor overall survival rates, reinforcing the necessity to detect OSCC early. The scope of the current review is to provide an update on OSCC in patients with FA.
Assuntos
Anemia de Fanconi/complicações , Anemia de Fanconi/epidemiologia , Neoplasias Bucais/epidemiologia , Neoplasias Bucais/etiologia , Terapia Combinada , Gerenciamento Clínico , Suscetibilidade a Doenças , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/etiologia , Predisposição Genética para Doença , Humanos , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/terapia , Fatores de Risco , Resultado do TratamentoRESUMO
High-risk human papillomaviruses (HPVs) deregulate epidermal differentiation and cause anogenital and head and neck squamous cell carcinomas (SCCs). The E7 gene is considered the predominant viral oncogene and drives proliferation and genome instability. While the implementation of routine screens has greatly reduced the incidence of cervical cancers which are almost exclusively HPV positive, the proportion of HPV-positive head and neck SCCs is on the rise. High levels of HPV oncogene expression and genome load are linked to disease progression, but genetic risk factors that regulate oncogene abundance and/or genome amplification remain poorly understood. Fanconi anemia (FA) is a genome instability syndrome characterized at least in part by extreme susceptibility to SCCs. FA results from mutations in one of 15 genes in the FA pathway, whose protein products assemble in the nucleus and play important roles in DNA damage repair. We report here that loss of FA pathway components FANCA and FANCD2 stimulates E7 protein accumulation in human keratinocytes and causes increased epithelial proliferation and basal cell layer expansion in the HPV-positive epidermis. Additionally, FANCD2 loss stimulates HPV genome amplification in differentiating cells, demonstrating that the intact FA pathway functions to restrict the HPV life cycle. These findings raise the possibility that FA genes suppress HPV infection and disease and suggest possible mechanism(s) for reported associations of HPV with an FA cohort in Brazil and for allelic variation of FA genes with HPV persistence in the general population.
Assuntos
Proteína do Grupo de Complementação A da Anemia de Fanconi/metabolismo , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Genoma Viral/fisiologia , Papillomavirus Humano 16/fisiologia , Proteínas E7 de Papillomavirus/metabolismo , Infecções por Papillomavirus/metabolismo , Replicação Viral/fisiologia , Brasil/epidemiologia , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Linhagem Celular Transformada , Anemia de Fanconi/epidemiologia , Anemia de Fanconi/genética , Anemia de Fanconi/metabolismo , Anemia de Fanconi/patologia , Anemia de Fanconi/virologia , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Feminino , Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Queratinócitos/metabolismo , Queratinócitos/patologia , Queratinócitos/virologia , Masculino , Proteínas E7 de Papillomavirus/genética , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/patologiaRESUMO
A 38-year-old female of African-Caribbean origin presented with symptomatic anemia and was found to have hypoplastic thumbs and patchy hypopigmentation. Peripheral blood examination revealed pancytopenia and the bone marrow biopsy confirmed marrow hypoplasia. Fanconi anemia was later confirmed by flow cytometry and diepoxybutane testing. Treatment was limited to transfusions after development of toxicity with cyclosporine and androgen therapy. She manifested classical features of transfusion-related hemosiderosis and died 12 years after initial presentation.
Assuntos
Anemia de Fanconi/diagnóstico , Adulto , Idade de Início , Transfusão de Sangue , Anemia de Fanconi/epidemiologia , Anemia de Fanconi/terapia , Feminino , Humanos , Quelantes de Ferro/uso terapêutico , Jamaica , Polegar/anormalidadesRESUMO
Fanconi anemia (FA) is an autosomal recessive genetic disease characterized by progressive bone marrow failure, susceptibility to cancer and multiple congenital anomalies. There is important clinical variability among patients and the knowledge of factors which might predict outcome would greatly help the decision making regarding the choices of treatment and the appropriate time to start it. Future studies of the possible correlation between specific mutations with specific clinical presentations will provide the answer to one of these factors. At our Center we standardized a rapid and precise screening test using a mismatch PCR assay for a specific mutation (3788-3790del in exon 38 of gene FANCA) in Brazilian FA patients. We present the results obtained after screening 80 non-consanguineous FA patients referred from all regions of Brazil with a clinical diagnosis of FA supported by cellular hypersensitivity to diepoxybutane. We were able to detect the 3788-3790del allele in 24 of the 80 (30%) FA patients studied. Thirteen of the 80 (16.25%) were homozygotes and 11 of the 80 (13.75%) were compound heterozygotes, thus confirming the high frequency of the FANCA 3788-3790del mutation in Brazilian FA patients. The identification of patients with specific mutations in the FA genes may lead to a better clinical description of this condition, also providing data for genotype-phenotype correlations, to a better understanding of the interaction of this specific mutation with other mutations in compound heterozygote patients, and ultimately to the right choices of treatment for each patient with improvement of the prognosis on future studies.
Assuntos
Éxons/genética , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Anemia de Fanconi/genética , Mutação/genética , Adolescente , Adulto , Brasil/epidemiologia , Criança , Pré-Escolar , Anemia de Fanconi/epidemiologia , Deleção de Genes , Marcadores Genéticos , Testes Genéticos , Heterozigoto , Humanos , Reação em Cadeia da PolimeraseRESUMO
Fanconi anemia (FA) is an autosomal recessive genetic disease characterized by progressive bone marrow failure, susceptibility to cancer and multiple congenital anomalies. There is important clinical variability among patients and the knowledge of factors which might predict outcome would greatly help the decision making regarding the choices of treatment and the appropriate time to start it. Future studies of the possible correlation between specific mutations with specific clinical presentations will provide the answer to one of these factors. At our Center we standardized a rapid and precise screening test using a mismatch PCR assay for a specific mutation (3788-3790del in exon 38 of gene FANCA) in Brazilian FA patients. We present the results obtained after screening 80 non-consanguineous FA patients referred from all regions of Brazil with a clinical diagnosis of FA supported by cellular hypersensitivity to diepoxybutane. We were able to detect the 3788-3790del allele in 24 of the 80 (30 percent) FA patients studied. Thirteen of the 80 (16.25 percent) were homozygotes and 11 of the 80 (13.75 percent) were compound heterozygotes, thus confirming the high frequency of the FANCA 3788-3790del mutation in Brazilian FA patients. The identification of patients with specific mutations in the FA genes may lead to a better clinical description of this condition, also providing data for genotype-phenotype correlations, to a better understanding of the interaction of this specific mutation with other mutations in compound heterozygote patients, and ultimately to the right choices of treatment for each patient with improvement of the prognosis on future studies.